Previously known approaches to dealing with epidemiological outbreaks of transmittable clinical diseases have traditionally focused on three approaches: isolation of affected individuals; use of antimicrobial agents, and use of vaccinations. Antimicrobial agents have been used successfully for treatment once the pathogen has been identified; however, if the microorganism is resistant to the antimicrobial agent, there are limited or no options other than relying on the patient's own immune system for recovery or survival (in the case of life-threatening infections).
Individuals have been routinely protected by vaccinating, or immunizing, against an attenuated bacterial or viral strain where the vaccine has demonstrated good efficacy in prior tests. The underlying flaws of vaccinations are its safety, lack of protection against diverse strains causing the disease, availability of sufficient supplies of the vaccine, and most importantly, administration of the vaccine in sufficient time prior to infection to elicit an immune response in the patient against the pathogen. Unfortunately, in the event that the population is not vaccinated by the time an outbreak reaches epidemic proportions, a vaccination program that requires multiple injections over a significant period of time would have very limited effectiveness in protecting the population. In addition, individuals having impaired immunity (i.e., are immunodeficient) would be unable to generate an effective response. Moreover, given the high cost of a broad vaccination program, the general population has been vaccinated to only a limited number of pathogens. The rise of numerous emerging infectious diseases and the threat of bioterrorism acts have significantly elevated the susceptibility of large populations to a potentially epidemic disease outbreak.
Another approach, which has been referred to as “passive therapeutic immunity,” to dealing with infection is the use of therapeutic antibodies for the treatment of pathogenic agents that are incurable by antimicrobial agents. Passive therapeutic immunity may also be used for individuals who have not been previously vaccinated. For example, the use of therapeutic antibodies has been reported with different degrees of protection against anthrax, biological toxins, brucellosis, Q fever, plague, smallpox, tularemia, viral encephalitides, and viral hemorrhagic fevers. Recent work has focused on the use of monoclonal antibodies, particularly because they can be produced in cell culture in large quantities once the hybridoma cell line is isolated. Alternatively, a recombinant mouse monoclonal antibody can be engineered with human sequences (generally referred to as a “humanized antibody”) and produced in large quantities, albeit at expensive costs that may be prohibitory for broad use.
A severe drawback of the use of monoclonal antibodies is that they recognize only a single site or epitope on the microorganism, which is not as effective as polyclonal antibodies that recognize multiple sites. For example, previous testing using anthrax polyclonal sera containing antibodies to several sites demonstrated protective efficacy of the polyclonal antibodies. However, when the same test was performed using monoclonal antibodies, only one of four monoclonal antibodies tested conferred protection. Another limitation of monoclonal antibody treatment is that monoclonal antibodies offer limited protection to pathogens where the epitope is not conservatively maintained, such as a pathogen having numerous species or viral pathogens that prone to a higher mutation frequency.
West Nile Virus is a specific example of a disease where treatment after contacting the disease shows little efficacy. Specifically, it is recognized in the art that there is not yet any experimental evidence that therapy with immunoglobulin will improve survival or neurological outcome of experimental animals when this therapy is initiated after the development of the clinical neurological disease. Further, no studies, either prophylactic for protection or post-infection for therapy, have demonstrated effectiveness of immunoglobulin treatment in animals that become infected by natural transmission of West Nile Virus.
Published U.S. Patent Application 2003/0211110 to Shimoni et al. discloses that hyperimmune sera collected from humans was able to facilitate the recovery of two immunocompromised patients tested positive by West Nile Virus upon continuous treatment with antibody delivered intravenously. In a separate report by Jackson, Can. J. Neurol. Sci., 2004, however, a patient showed no beneficial effect upon similar treatment. It is therefore unclear whether the specified treatment alone was responsible for the recovery of the patients, and more so, if immunosuppression was a key factor required for treatment.
In light of the above, it is clear that further, more effective methods of treating and preventing infection, particularly by a transmittable viral disease, are needed. The present invention provides pharmaceutical compositions and methods of preparation and use thereof that are particularly beneficial for treating and preventing such infection.